Our investigations are directed at the mechanisms of drug resistance and red blood cell invasion by the malaria parasite Plasmodium falciparum. Chloroquine-resistant strains of P. falciparum counter the drug by expelling it rapidly via an unknown mechanism. Genetic linkage analysis has shown that chloroquine resistance is controlled by a single gene or closely linked group of genes with an approximately 200 kilobase segment on the parasite's seventh chromosome. Characterization of genes within this segment should lead to an understanding of the rapid efflux mechanism. Point mutations in the dihydrofolate reductase (DHFR) inhibitors, pyrimethamine and cycloguanil, depending upon the position of the mutations and the residues involved. The Asn-108 mutation plays a central role in pyrimethamine resistance. A survey has shown approximately 90 percent incidence of this mutation in a wide section of the Brazilian Amazon, consistent with pyrimethamine failure rates. A structural analog of cycloguanil has high activity against pyrimethamine- and cycloguanil- resistant forms of P. falciparum, suggesting that it may be possible to develop alternative DHFR inhibitors as drugs. A switch to an alternative pathway of red cell invasion has been detected in a P. falciparum clone made to propagate in neuraminidase-treated, sialic acid-deficient red blood cells. The switch may involve a mechanism in which certain genes are activated or rearranged. Differential and subtractive screening methods are being used to search for these genes.